Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

Abstract

// Polina Matre 1, * , Juliana Velez 1, * , Rodrigo Jacamo 1 , Yuan Qi 2 , Xiaoping Su 2 , Tianyu Cai 1 , Steven M. Chan 3 , Alessia Lodi 4 , Shannon R. Sweeney 4 , Helen Ma 1 , Richard Eric Davis 5 , Natalia Baran 1 , Torsten Haferlach 6 , Xiaohua Su 7 , Elsa Renee Flores 7 , Doriann Gonzalez 1 , Sergej Konoplev 8 , Ismael Samudio 9 , Courtney DiNardo 1 , Ravi Majeti 3 , Aaron D. Schimmer 10 , Weiqun Li 11 , Taotao Wang 11 , Stefano Tiziani 4 , Marina Konopleva 1 1 Departments of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA 4 Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA 5 Lymphoma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 CEO of MLL Munich Leukemia Laboratory, Munich, Germany 7 Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 8 Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 The Centre for Drug Research and Development Biologics, Vancouver, British Columbia, Canada 10 Medical Biophysics, Princess Margaret Hospital / Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada 11 Analytical Chemistry, Pharmacology, Spectroscopy, Calithera Biosciences, South San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Marina Konopleva, email: mkonople@mdanderson.org Keywords: leukemia, metabolism, glutamine, microenvironment, differentiation therapy Received: June 08, 2016     Accepted: October 13, 2016     Published: October 27, 2016 ABSTRACT Metabolic reprogramming has been described as a hallmark of transformed cancer cells. In this study, we examined the role of the glutamine (Gln) utilization pathway in acute myeloid leukemia (AML) cell lines and primary AML samples. Our results indicate that a subset of AML cell lines is sensitive to Gln deprivation. Glutaminase (GLS) is a mitochondrial enzyme that catalyzes the conversion of Gln to glutamate. One of the two GLS isoenzymes, GLS1 is highly expressed in cancer and encodes two different isoforms: kidney (KGA) and glutaminase C (GAC). We analyzed mRNA expression of GLS1 splicing variants, GAC and KGA, in several large AML datasets and identified increased levels of expression in AML patients with complex cytogenetics and within specific molecular subsets. Inhibition of glutaminase by allosteric GLS inhibitor bis -2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide or by novel, potent, orally bioavailable GLS inhibitor CB-839 reduced intracellular glutamate levels and inhibited growth of AML cells. In cell lines and patient samples harboring IDH1/IDH2 (Isocitrate dehydrogenase 1 and 2) mutations, CB-839 reduced production of oncometabolite 2-hydroxyglutarate, inducing differentiation. These findings indicate potential utility of glutaminase inhibitors in AML therapy, which can inhibit cell growth, induce apoptosis and/or differentiation in specific leukemia subtypes.